+

WO1998015549A1 - Composes azaheterocycliques n-substitues - Google Patents

Composes azaheterocycliques n-substitues Download PDF

Info

Publication number
WO1998015549A1
WO1998015549A1 PCT/DK1997/000420 DK9700420W WO9815549A1 WO 1998015549 A1 WO1998015549 A1 WO 1998015549A1 DK 9700420 W DK9700420 W DK 9700420W WO 9815549 A1 WO9815549 A1 WO 9815549A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
pharmaceutically acceptable
pharmaceutical composition
ylidene
acceptable salt
Prior art date
Application number
PCT/DK1997/000420
Other languages
English (en)
Inventor
Henrik Sune Andersen
Tine Krogh JØRGENSEN
Rolf Hohlweg
Knud Erik Andersen
Zdenek Polivka
Frantisek Miksik
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA99003106A priority Critical patent/MXPA99003106A/es
Priority to IL12912197A priority patent/IL129121A/en
Priority to AT97941882T priority patent/ATE240320T1/de
Priority to PL97332592A priority patent/PL332592A1/xx
Priority to EP97941882A priority patent/EP0934313B1/fr
Priority to CA002267691A priority patent/CA2267691A1/fr
Priority to DE69722022T priority patent/DE69722022D1/de
Priority to BR9712204-1A priority patent/BR9712204A/pt
Priority to HU9904705A priority patent/HUP9904705A3/hu
Priority to AU43770/97A priority patent/AU740958B2/en
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP10517091A priority patent/JP2001501937A/ja
Publication of WO1998015549A1 publication Critical patent/WO1998015549A1/fr
Priority to NO991564A priority patent/NO991564L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel N-substituted azaheterocyclic carboxylic acids in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions.
  • the invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin, the present compounds being known to interfere with neuropeptide containing C-fibres.
  • the present compounds can be used in the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) in order to improve the glucose tolerance as well as ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the nervous system exerts a profound effect on the inflammatory response.
  • Antidromic stimulation of sensory nerves results in localised vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31 , 138-151), and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastrointestinal and respiratory tracts.
  • inhibition of sensory nerve peptide release and/or activity may be useful in treatment of for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine.
  • CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993).
  • This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or ageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased.
  • inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or ageing.
  • the present invention relates to compounds of the general formula I, wherein X, Y, Z, R 1 , R 2 and r are as defined in the detailed part of the present description.
  • the present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis
  • a method of treating indications caused by or related to the secretion and circulation of insulin antagonising peptides e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the method of treating may be described as the treatment of one of the above indications in a subject in need thereof, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides, e.g. non-insulin-dependent diabetes mellitus (NIDDM) and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the present invention relates to novel N-substituted azaheterocyclic carboxylic acids of formula I
  • R 1 and R 2 independently are hydrogen, halogen or C 1-6 -alkyl
  • X is -S-, -CH 2 CH 2 -, -O-CH 2 -, -CH 2 -O-, -S-CH 2 -, -CH 2 -S-; and r is 1 or 2 ;
  • R 3 is -(CH 2 ) p COOH wherein p is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
  • the compounds of formula I exist as the individual geometric or optical isomers.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts, metal salts or, optionally alkylated, ammonium salts.
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by precipitation or crystallisation.
  • the compounds of formula I may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
  • C ⁇ -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1 ,2-dimethylpropyl, 2,2- dimethylpropyl and 1 ,2,2-trimethylpropyl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of histamine induced paw oedema Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995) in which the novel compounds of formula I exhibit a potent inhibitory effect.
  • Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
  • Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post- herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
  • neuropathy diabetic, post-traumatic, toxic
  • neuralgia rheumatoid arthritis
  • spondylitis gout
  • inflammatory bowel disease exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, g
  • the compounds of general formula I improve the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings.
  • the compounds of general formula I may be used in the treatment of NIDDM as well as ageing-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula I.
  • the compounds of formula I may be prepared by the following method:
  • a compound of formula II wherein R 1 , R 2 , X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an aza compound of formula III wherein Z is as defined above.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride or potassium carbonate and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
  • a base e.g. sodium hydride or potassium carbonate
  • a catalyst e.g. an alkali metal iodide at
  • the carboxylic acid group can, for example, be esterified. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry” J.F.W. McOrnie ed. (New York, 1973).
  • the rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995). In brief 250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and placed on a 32 degree(Celsius) heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes hereafter the paw swelling was determined by water plethysmography (Ugo Basile). Test compounds were administered intraperitoneally at 15 minutes before the anaesthetics.
  • mice 16 weeks of age, where injected glucose (2g/kg) subcutaneously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • glucose oxidase method was determined in tail venous blood by the glucose oxidase method.
  • mice were decapitated and trunk blood collected.
  • Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
  • the present invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • compositions containing the compounds of this invention may be prepared by conventional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral, nasal, pulmonary or parenteral e.g. rectal, depot, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation can be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound (as free compound or salt thereof) 100 mg
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role such as e.g. neurogenic pain, inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, such as non-insulin-dependent diabetes mellitus (NIDDM) or ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, in an effective amount.
  • dosages suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutical carrier or diluent.
  • Suitable dosage ranges varies as indicated above depending as usual upon the exact mode of administration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of this invention are dispensed in unit dosage form comprising 50- 200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • TLC thin layer chromatography
  • CDCI 3 deuterio chloroform
  • DMSO-d 6 hexadeuterio dimethylsulfoxide.
  • the structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate.
  • 1 H NMR shifts ( ⁇ H ) are given in parts per million (ppm).
  • M.p. is melting point and is given in °C and is not corrected.
  • Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385).
  • Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
  • the reaction mixture was diluted with chloroform (100 ml), the solid was filtered off and the filtrate was washed with water (3 x 80 ml).
  • the chloroform solution was dried (MgSO 4 ) and the solvent removed in vacuo.
  • the oily residue (5.6 g) was dissolved in acetone and treated with an ethanolic solution of oxalic acid.
  • the crude hydrogen oxalate (5.8 g) was filtered off and washed with a hot mixture of ethanol and acetone.
  • the reaction mixture was diluted with benzene (100 ml), the solid was filtered off and the filtrate was washed with water (4 x 60 ml).
  • the benzene solution was dried (MgSO 4 ) and the solvent removed in vacuo.
  • the oily residue (6.34 g) was dissolved in acetone and treated with an ethanolic solution of oxalic acid.
  • the reaction mixture was diluted with benzene (300 ml), the solid was filtered off and the filtrate was washed with water (5 x 80 ml).
  • the benzene solution was dried (MgS0 4 ) and the solvent removed in vacuo.
  • the oily residue (6.83 g) was dissolved in acetone and treated with a solution of oxalic acid in ethanol.
  • HPLC retention time 20.07 and 20.26 minutes (mixture of E/Z-isomers)(5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 25 minutes at 35 °C).
  • HPLC retention time 18.91 and 19.06 minutes (mixture of E/Z-isomers)(5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 25 minutes at 35 °C.
  • the aqueous phase was basified with 50 % sodium hydroxide and extracted with diethyl ether (2 x 100 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (100 ml), dried (MgS0 4 ), filtered and the solvent was evaporated in vacuo. This afforded 0.50 g (41 %) of 1-(3-(6,1 1-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-propyl)-4-piperidinecarboxylic acid ethyl ester as an oil.
  • HPLC retention time 17.27 minutes (5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 25 minutes at 35 °C.
  • HPLC retention time 20.13 minutes (5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 30 minutes at 35 °C).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne des acides carboxyliques azahétérocycliques N-substitués nouveaux, représentés par la formule générale (I), dans laquelle X, Y, Z, R1, R2 et r sont tels que définis dans la partie détaillée de la description, ou des sels desdits acides. L'invention concerne également des procédés de fabrication desdits acides, des compositions les contenant et l'utilisation desdits acides dans le traitement clinique d'états douloureux, hyperalgésiques et/ou inflammatoires, dans lesquels des fibres C jouent un rôle pathophysiologique en déclenchant une douleur ou une inflammation neurogènes. L'invention concerne enfin l'utilisation desdits acides dans le traitement d'indications qui sont causées par la sécrétion et la circulation de peptides antagonistes de l'insuline ou qui sont liées.
PCT/DK1997/000420 1996-10-04 1997-10-02 Composes azaheterocycliques n-substitues WO1998015549A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
HU9904705A HUP9904705A3 (en) 1996-10-04 1997-10-02 N-substituted azaheterocyclic carboxylic acid derivatives and pharmaceutical compositions containing them
AT97941882T ATE240320T1 (de) 1996-10-04 1997-10-02 N-substituierte azaheterocyclische verbindungen
PL97332592A PL332592A1 (en) 1996-10-04 1997-10-02 N-substituted azaheterocyclic compounds
EP97941882A EP0934313B1 (fr) 1996-10-04 1997-10-02 Composes azaheterocycliques n-substitues
CA002267691A CA2267691A1 (fr) 1996-10-04 1997-10-02 Composes azaheterocycliques n-substitues
MXPA99003106A MXPA99003106A (es) 1996-10-04 1997-10-02 Compuestos azaheterociclicos n-sustituidos.
BR9712204-1A BR9712204A (pt) 1996-10-04 1997-10-02 Composto, processos para preparar um composto, tratar inflamacão neurogênica e artrite reumatóide, composicão farmaceutica, composições farmacêuticas adequadas para tratar inflamacão neurogênica, para tratar neuropatia, para tratar artrite reumatóide, para reduzir glicose do sangue, para inibir a atividade do cgrp, para tratar enxaqueca, para tratar coceira, e uso de um composto
DE69722022T DE69722022D1 (de) 1996-10-04 1997-10-02 N-substituierte azaheterocyclische verbindungen
AU43770/97A AU740958B2 (en) 1996-10-04 1997-10-02 N-substituted azaheterocyclic compounds
IL12912197A IL129121A (en) 1996-10-04 1997-10-02 Nitrogen-converted azathrocyclic compounds, pharmaceutical preparations containing them and their use in the preparation of pharmaceutical preparations
JP10517091A JP2001501937A (ja) 1996-10-04 1997-10-02 Ｎ―置換化アザ複素環式化合物
NO991564A NO991564L (no) 1996-10-04 1999-03-30 N-substituerte azaheterosykliske forbindelser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1088/96 1996-10-04
DK108896 1996-10-04

Publications (1)

Publication Number Publication Date
WO1998015549A1 true WO1998015549A1 (fr) 1998-04-16

Family

ID=8100865

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1997/000420 WO1998015549A1 (fr) 1996-10-04 1997-10-02 Composes azaheterocycliques n-substitues

Country Status (21)

Country Link
US (1) US6004983A (fr)
EP (1) EP0934313B1 (fr)
JP (1) JP2001501937A (fr)
KR (1) KR20000048901A (fr)
CN (3) CN1084744C (fr)
AR (1) AR010237A1 (fr)
AT (1) ATE240320T1 (fr)
AU (1) AU740958B2 (fr)
BR (1) BR9712204A (fr)
CA (1) CA2267691A1 (fr)
CZ (1) CZ114299A3 (fr)
DE (1) DE69722022D1 (fr)
HU (1) HUP9904705A3 (fr)
IL (1) IL129121A (fr)
MX (1) MXPA99003106A (fr)
NO (1) NO991564L (fr)
PL (1) PL332592A1 (fr)
RU (1) RU2186769C2 (fr)
TW (1) TW420675B (fr)
WO (1) WO1998015549A1 (fr)
ZA (1) ZA978792B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006120010A3 (fr) * 2005-05-12 2007-01-18 Merckle Gmbh Dibenzocycloheptanes et agents pharmaceutiques contenant ces composes
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6613905B1 (en) * 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US7355042B2 (en) 2001-10-16 2008-04-08 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
CA2530444C (fr) * 2003-06-27 2012-03-13 Janssen Pharmaceutica, N.V. Modulateurs du recepteur opioide tricycliques
EP1910353A1 (fr) * 2004-08-05 2008-04-16 Janssen Pharmaceutica N.V. Modulateurs d opioïdes delta tricycliques
AU2005319061A1 (en) * 2004-12-22 2006-06-29 Janssen Pharmaceutica N.V. Tricyclic delta-opioid modulators
CA2592462A1 (fr) * 2004-12-22 2006-06-29 Janssen Pharmaceutica N.V. Modulateurs des recepteurs opioides delta tricycliques
CA2591963A1 (fr) * 2004-12-22 2006-06-29 Janssen Pharmaceutica N.V. Modulateurs des recepteurs opioides $g(d) tricycliques
CN101128460A (zh) * 2005-01-06 2008-02-20 詹森药业有限公司 三环的δ-阿片样物质调节剂
EP1896467B1 (fr) * 2005-06-16 2010-12-01 Janssen Pharmaceutica NV Modulateurs d'opioides tricycliques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018793A1 (fr) * 1994-01-04 1995-07-13 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1996031499A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Composes heterocycliques nouveaux
WO1996031498A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1997022338A1 (fr) * 1995-12-15 1997-06-26 Novo Nordisk A/S Nouveau procede

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2086013A1 (fr) * 1990-06-22 1991-12-23 Tatsuhiko Sano Derives de naphthothiopyranone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018793A1 (fr) * 1994-01-04 1995-07-13 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1996031499A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Composes heterocycliques nouveaux
WO1996031498A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1997022338A1 (fr) * 1995-12-15 1997-06-26 Novo Nordisk A/S Nouveau procede

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COLLECT. CZECH. CHEM. COMMUN., Volume 59, 1994, KAREL SINDELAR et al., "Antihistamine Substances. Tricyclic Analogues of N-(4,4-Diphenyl-3-Butene-1-Yl)Nipecotic Acid and Some Related Compounds". *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
WO2006120010A3 (fr) * 2005-05-12 2007-01-18 Merckle Gmbh Dibenzocycloheptanes et agents pharmaceutiques contenant ces composes

Also Published As

Publication number Publication date
AU740958B2 (en) 2001-11-15
CN1191233C (zh) 2005-03-02
IL129121A0 (en) 2000-02-17
BR9712204A (pt) 1999-08-31
HUP9904705A3 (en) 2000-09-28
NO991564L (no) 1999-06-04
NO991564D0 (no) 1999-03-30
CN1084744C (zh) 2002-05-15
ATE240320T1 (de) 2003-05-15
PL332592A1 (en) 1999-09-27
RU2186769C2 (ru) 2002-08-10
CA2267691A1 (fr) 1998-04-16
KR20000048901A (ko) 2000-07-25
HUP9904705A2 (hu) 2000-06-28
IL129121A (en) 2004-03-28
AU4377097A (en) 1998-05-05
CN1403445A (zh) 2003-03-19
CN1403454A (zh) 2003-03-19
CN1235603A (zh) 1999-11-17
MXPA99003106A (es) 2004-12-02
CN1198820C (zh) 2005-04-27
EP0934313B1 (fr) 2003-05-14
JP2001501937A (ja) 2001-02-13
DE69722022D1 (de) 2003-06-18
AR010237A1 (es) 2000-06-07
CZ114299A3 (cs) 1999-09-15
TW420675B (en) 2001-02-01
ZA978792B (en) 1998-04-06
EP0934313A1 (fr) 1999-08-11
US6004983A (en) 1999-12-21

Similar Documents

Publication Publication Date Title
US6569849B1 (en) N-Substituted azaheterocyclic compounds
US6040318A (en) Tricycle substituted with azaheterocyclic carboxylic acids
US6054458A (en) Heterocyclic compounds
US6004983A (en) N-substituted azaheterocyclic compounds
US5780486A (en) Heterocyclic compounds
EP0851865B1 (fr) Derives de 12H-Dibenzo[d,g][1,3]dioxocines
US6060468A (en) N-substituted azaheterocyclic compounds
EP0869954B1 (fr) Composes heterocycliques utiles dans le traitement d'une inflammation neurogenique
EP0820443B1 (fr) Composes heterocycliques pour le traitement du diabete
WO1996031471A1 (fr) Nouveau procede

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 97199197.9

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1997941882

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV1999-1142

Country of ref document: CZ

Ref document number: PA/a/1999/003106

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2267691

Country of ref document: CA

Ref document number: 2267691

Country of ref document: CA

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 1998 517091

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1019997002931

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1997941882

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1999-1142

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019997002931

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 1997941882

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: PV1999-1142

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: 1019997002931

Country of ref document: KR

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载